Cerebral amyloid angiopathy (CAA) is an age-associated condition in which amyloid is deposited in the medial layer of primarily small- and medium-sized arteries and arterioles of the cerebral cortex and leptomeninges and is present in most patients with Alzheimer's disease (AD) and certain related disorders including hereditary cerebral hemorrhage with amyloidosis Dutch-type (HCHWA-D). The overall hypothesis of this proposal is that age and other risk factor-related changes in cerebrovascular smooth muscle cells renders them more susceptible to the pathogenic effects of Abeta resulting in CAA-related pathology. We plan to utilize novel and unique cell culture and transgenic model systems to investigate the role of age and other risk factors in the development of the smooth muscle cellular pathology of CAA. The studies outlined in this proposal will shed light on the roles of specific molecules, and age-related changes in these molecules, that could contribute to CAA pathology. The specific aims are as follows: First, we will determine if cultured cerebrovascular smooth muscle (CSM) cells from younger and aged comparisons with cultured CSM cells from young and aged non-human primates that develop pronounced or mild CAA (squirrel monkey or rhesus monkey, respectively). Second, we will determine the pathogenic effects of Abeta in cultured CSM cells obtained from control non-transgenic and wild-type or HCHWA-D mutant human AbetaPP transgenic mice. This will ascertain if over-expression of human Abeta PP affects the pathologic leads to earlier and/or more extensive cerebrovascular Abeta deposition and accompanying CAA-related pathology in our human Abeta PP transgenic mice. Lastly, we will determine if over-expression of RAGE influences the pathogenic effects of Abeta in cultured CSM cells obtained from RAGE transgenic mice and RAGE/human Abeta PP pathologic responsiveness of these cells to Abeta. These combined investigations will provide information about how age and changes in key molecules in CSM cells are involved in the development of CAA-related pathology.